PROJECT SUMMARY In this proposal, we plan to use a Complex Systems Biology approach to characterize the global microbiome and metabolome of various wounds over a longitudinal period of time. In addition, these global profiles will be integrated with an analysis of innate immune potential for activation. The research proposed here has the potential to uncover how the microbiome and innate immune responses influence the wound metabolic landscape and to generate insights into novel, low-cost therapeutic interventions that exploit microbial metabolic pathways or host cell metabolic immunomodulation changes. The ultimate goal is to develop evidence-based, medical countermeasure protocols that could be initiated in the clinic and followed by an outpatient population. By 2050, the American Diabetes Foundation predicts that one in three adults in the United States will have diabetes, correlating to a significant immunocompromised population and nearly 85 million patients subjected to loss of a limb as a result of a non-healing chronic wound. With this research, we will not only gain significant insight in to the basic biology of host-pathogen interactions within the chronic wound environment in diabetics, but will also lay the foundation for novel medical interventions predictive of wound healing.